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- EMDB-28067: CryoEM reconstruction of tri-specific 298-52-80 Multabody (no sym... -

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Basic information

Entry
Database: EMDB / ID: EMD-28067
TitleCryoEM reconstruction of tri-specific 298-52-80 Multabody (no symmetry applied)
Map datacryoEM half map of tri-specific 298-52-80 Multabody
Sample
  • Complex: tri-specific 298-52-80 Multabody
Keywordsnanoparticle / SARS-CoV-2 / antibody / ANTIVIRAL PROTEIN
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.35 Å
AuthorsKucharska I / Cui H / Rubinstein JL / Julien JP
Funding support Canada, United States, 6 items
OrganizationGrant numberCountry
Ontario Early Researcher Awards Canada
Canada Research Chairs Canada
Natural Sciences and Engineering Research Council (NSERC, Canada)6280100058 Canada
Canadian Institutes of Health Research (CIHR)PJ4-169662 Canada
Other governmentCOVID-19 Research Fund
Bill & Melinda Gates FoundationINV-023398 United States
CitationJournal: Sci Transl Med / Year: 2023
Title: A multi-specific, multi-affinity antibody platform neutralizes sarbecoviruses and confers protection against SARS-CoV-2 in vivo.
Authors: Clare Burn Aschner / Krithika Muthuraman / Iga Kucharska / Hong Cui / Katherine Prieto / Manoj S Nair / Maple Wang / Yaoxing Huang / Natasha Christie-Holmes / Betty Poon / Jessica Lam / ...Authors: Clare Burn Aschner / Krithika Muthuraman / Iga Kucharska / Hong Cui / Katherine Prieto / Manoj S Nair / Maple Wang / Yaoxing Huang / Natasha Christie-Holmes / Betty Poon / Jessica Lam / Azmiri Sultana / Robert Kozak / Samira Mubareka / John L Rubinstein / Edurne Rujas / Bebhinn Treanor / David D Ho / Arif Jetha / Jean-Philippe Julien /
Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), has been responsible for a global pandemic. Monoclonal antibodies (mAbs) have ...Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), has been responsible for a global pandemic. Monoclonal antibodies (mAbs) have been used as antiviral therapeutics; however, these therapeutics have been limited in efficacy by viral sequence variability in emerging variants of concern (VOCs) and in deployment by the need for high doses. In this study, we leveraged the multi-specific, multi-affinity antibody (Multabody, MB) platform, derived from the human apoferritin protomer, to enable the multimerization of antibody fragments. MBs were shown to be highly potent, neutralizing SARS-CoV-2 at lower concentrations than their corresponding mAb counterparts. In mice infected with SARS-CoV-2, a tri-specific MB targeting three regions within the SARS-CoV-2 receptor binding domain was protective at a 30-fold lower dose than a cocktail of the corresponding mAbs. Furthermore, we showed in vitro that mono-specific MBs potently neutralize SARS-CoV-2 VOCs by leveraging augmented avidity, even when corresponding mAbs lose their ability to neutralize potently, and that tri-specific MBs expanded the neutralization breadth beyond SARS-CoV-2 to other sarbecoviruses. Our work demonstrates how avidity and multi-specificity combined can be leveraged to confer protection and resilience against viral diversity that exceeds that of traditional monoclonal antibody therapies.
History
DepositionSep 8, 2022-
Header (metadata) releaseMay 24, 2023-
Map releaseMay 24, 2023-
UpdateDec 6, 2023-
Current statusDec 6, 2023Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_28067.png

Downloads & links

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Map

FileDownload / File: emd_28067.map.gz / Format: CCP4 / Size: 93 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationcryoEM half map of tri-specific 298-52-80 Multabody
Voxel sizeX=Y=Z: 1.04 Å
Density
Contour LevelBy AUTHOR: 2.1
Minimum - Maximum-3.8289223 - 6.564061
Average (Standard dev.)0.011713239 (±0.28064)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions290290290
Spacing290290290
CellA=B=C: 301.59998 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: half map of tri-specific 298-52-80 Multabody

Fileemd_28067_half_map_1.map
Annotationhalf map of tri-specific 298-52-80 Multabody
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: half map of tri-specific 298-52-80 Multabody

Fileemd_28067_half_map_2.map
Annotationhalf map of tri-specific 298-52-80 Multabody
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : tri-specific 298-52-80 Multabody

EntireName: tri-specific 298-52-80 Multabody
Components
  • Complex: tri-specific 298-52-80 Multabody

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Supramolecule #1: tri-specific 298-52-80 Multabody

SupramoleculeName: tri-specific 298-52-80 Multabody / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration2.0 mg/mL
BufferpH: 7.4
Component:
ConcentrationFormulaName
137.0 mmol/LNaClSodium chlorideSodium chloride
2.7 mmol/LKClPotassium chloride
10.0 mmol/LNa2HPO4Disodium phosphate
1.8 mmol/LKH2PO4Monopotassium phosphate
GridModel: Homemade / Material: GOLD / Mesh: 400 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 15 sec. / Pretreatment - Atmosphere: AIR
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Cs: 2.7 mm / Nominal defocus max: 1.5 µm / Nominal defocus min: 0.5 µm / Nominal magnification: 75000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Number real images: 4385 / Average exposure time: 8.31 sec. / Average electron dose: 49.58 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 955995
Startup modelType of model: NONE
Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: NOT APPLICABLE
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Algorithm: FOURIER SPACE / Resolution.type: BY AUTHOR / Resolution: 2.35 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 3) / Number images used: 151443

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